WO1998045411A1 - Cell culture media for enhanced protein production - Google Patents
Cell culture media for enhanced protein production Download PDFInfo
- Publication number
- WO1998045411A1 WO1998045411A1 PCT/US1998/006800 US9806800W WO9845411A1 WO 1998045411 A1 WO1998045411 A1 WO 1998045411A1 US 9806800 W US9806800 W US 9806800W WO 9845411 A1 WO9845411 A1 WO 9845411A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cell
- culture medium
- amino acids
- medium
- cell culture
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/26—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against hormones ; against hormone releasing or inhibiting factors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/42—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins
- C07K16/4283—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an allotypic or isotypic determinant on Ig
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/44—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material not provided for elsewhere, e.g. haptens, metals, DNA, RNA, amino acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/0018—Culture media for cell or tissue culture
- C12N5/0037—Serum-free medium, which may still contain naturally-sourced components
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2500/00—Specific components of cell culture medium
- C12N2500/30—Organic components
- C12N2500/32—Amino acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2500/00—Specific components of cell culture medium
- C12N2500/30—Organic components
- C12N2500/34—Sugars
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2500/00—Specific components of cell culture medium
- C12N2500/30—Organic components
- C12N2500/38—Vitamins
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2500/00—Specific components of cell culture medium
- C12N2500/60—Buffer, e.g. pH regulation, osmotic pressure
Definitions
- This invention relates to cell culture media, which improves protein production, constrains cell growth and extends cell longevity jln vitro culture, and to methods for the production and use of such media.
- the increasing demand for monoclonal antibodies (MABs) useful in research, diagnosis, therapy and purification purposes has created a need to optimize production techniques.
- the prior art includes improved bioreactor designs and bioreactor operation to increase cell densities or the longevity of the culture by nutrient feedings .
- Bioreactors have been operated in fed-batch, immobilized, perfusion and continuous modes. Alternate strategies, such as the use of temperature, media formulation, including the addition of mouse peritoneal factors, growth inhibitors, autocrine factors or cyclic mononucleotides and hyperstimulation by osmolarity stress, have been used to enhance protein production. These approaches have shown only marginal success .
- CMOS basal cell culture media
- RPMI 1640 DMEM (Dulbecco's modified Eagle's medium), Ham's F12 and DMEM/F12
- DF DMEM/F12
- Murakami showed that doubling total amino acids or glucose alone did not increase cell density but concurrent elevation of amino acids and glucose maximized the cellular growth by threefold.
- Hyper-stimulation of monoclonal antibody production by high osmolarity stress in a eRDF medium is described in Chua et al . (1994) (2) and (1994) (3) .
- the maximum IgG concentration achieved was about 300 ug/ml and 270 ug/ml for HG11 and TBC3 cells, respectively, at medium osmolarities about 350 to 400 mOsm. Further increase in osmolarity with NaCl caused a deterioration in antibody production.
- the invention provides cell nutrient media which enhance protein production and prolong in vitro cell viability.
- the method cell culture utilizing such media are an important aspect of the invention.
- the media and the methods of the invention are applicable to the culture of cells of any type in bioreactors of all kinds.
- Figure 2a-2d reflect the result of hollow fiber bioreactor experiments in which BTC-28101 was utilized.
- Figure 2a represents levels of antibody produced.
- Figure 2b sets forth medium pH data.
- Figure 2c reports glucose utilization.
- Figure 2d reprots cell viability.
- Figure 3a growth of hybridoma 2HG11 in serum-free BTC-28101 and commercial media Hb and PFHM available from Gibco.
- Figure 3b IgG concentration in serum-free BTC-28101 and commercial media Hb and PFHM available from Gibco.
- Figure 4 growth of hybridomas 2HG11 and TBC3 in BTC-28102 and control DMEM/F12 media.
- Figure 5 growth of CHO cells in BTC-28103 and control IMDM media.
- IMDM refers to Iscove's Modified Dulbecco's Media.
- Figure 6 presents a correlation of percent dry weight of amino acid in the media components with MAB production in ug/ml . The figure illustrates an unexpected increase in MAB concentration when the percent amino acid content in the media exceeds about 20%.
- D/F refers to Dulbecco's Modified Eagle Medium: Nutrient Mixture F-12, 1:1 Mixture.
- Cell Culture Medium ny medium in which cells of any type may be cultured.
- Bioreactor Any device in which cells may be cultured. Includes stationary flasks, spinner flasks and hollow fiber bioreactors.
- Basal Medium cell culture medium that contains all of the ingredients essential to cell metabolism, e.g., amino acids, lipids, carbohydrates, vitamins and mineral salts.
- RPMI , DMEM, Ham's 12 and RDF are examples of basal media.
- Non-Essential Amino Acids Al, Asn, Asp, Gin, Gly, Ser.
- the invention provides a method for improving protein production in cultures of protein producing cells.
- the invention comprises culturing hybridomas antibody producing cells in a high osmolarity aqueous medium comprising a high concentration of amino acids, in particular the essential amino acids, and an energy source, such as glucose or sucrose.
- the medium is substantially saturated at around 40°C with an amino acid or acids essential to the metabolism of the culture cells.
- the medium of the invention contains 5.50 to 20 grams per liter of total or gross amino acids in solution or suspension and 5.50 to 20 grams per liter of a carbohydrate energy source, preferably glucose, in solution.
- the gross amino acids comprise at least 20%, preferably, from about 25% to about 50% of the total dry weight of the medium components.
- Cells may appropriately be adapted to the high osmolarity media of this invention by passaging.
- the osmolarity of the medium is from 320 to 450.
- Sodium chloride is the preferred osmolyte .
- the media and the methods of the invention are useful in all forms of bioreactors.
- the benefits of the invention are realized in static, batch, shaker flask, and spinner and hollow fiber bioreactor culture procedures .
- Cells of all kinds may be cultured in any of the methods of the invention.
- Culture of recombinant protein expression mammalian cells e.g., CHO cells
- Many types of mammalian cells, which contain recombinant protein containing expression vectors are known. See, e.g., Acklin, C . , et al . (Recombinant human brain-derived neurotrophic factor (THuBHDNF) . Disulfide structure and characterization of BDNF expressed in CHO cells) Int.J.Pept. Protein Res. (1993) 11:548-52; Fukushima, K. , et al .
- Medium BTC 28101 The dry powder form of Medium BTC-28101 was prepared as two separate components (A) and (B) as listed in Table I . The ingredients were milled to fine dry powder prior to use. To prepare the medium, Component (A) was dissolved in 90% by volume of pyrogen-free water. The mixture was warmed to around 40°C and stirred for one hour to fully dissolve the powder, and then cooled down to room temperature. Component (B) was added and stirred another hour to dissolve. pH was adjusted to 7.0 by addition of NaOH. Water was added to make up to the desired volume. The osmolarity of the medium was in the range of 330-335 mOsm/Kg. Table I - Composition of Medium BTC-28101 in mg/L
- D-Ca pantothenate 1.240 Linoleic acid 0.020
- composition of the medium BTC-28101 is
- This example compares cell growth and monoclonal antibody production in two hybridoma cell lines 2HG11
- the experiment was set up in shaker flasks with 100 ml media supplemented with 10% FBS (Fetal Bovine Serum) .
- Inoculum cells were adapted and maintained by daily passaging at 2xl0 5 /ml with the respective fresh medium for at least a week, and the viability of each inoculum culture was above 90% before use.
- Batch culture was started by inoculating at 2xl0 5 /ml into the respective medium. Samples were taken daily to follow the cell growth by trypan blue staining and hemocytometer counting. Monoclonal antibody concentration in the culture supernatant was determined by ELISA analysis. The effect on cell growth is shown in Fig. 1. Maximum concentration of Ig at the end of the cultures are summarized in Table II: Table II. Maximum Ig Concentration in the Cultures with BTC-28101 and Control DMEM/F12 Media
- Hybridoma cell line TH12 (anti-theophylline) was cultured in either the BTC-28101 media of Example 1 or a DMEM formulation. Cells were inoculated into 100 ml of BTC-28101 or control medium DMEM at 2X10 5 /ml in 250 ml spinner flasks, both media were supplemented with 10% FBS. Similar procedure as stated in Example 2 was followed for preparing the inoculum cultures, and for monitoring the batch. TH12 produced higher concentrations of antibody in BTC-28101 than in the formulation of DMEM. As Table III shows, cell numbers and cell viability were also higher in 28101.
- Table IV demonstrates enhanced Ig production and specific antibody titer when BTC-28101 is used.
- Ig concentrations determined by precipitating each sample with saturated ammonium sulfate and reading optical densities at 280 nm.
- Hybridoma cell line DI16 (anti-Dirofilaria immitis' was cultured in either the BTC-28101 or DMEM. DI16 produced higher concentrations of antibody in BTC-28101 than in the in-house formulation of DMEM. Table V shows that cell numbers and cell viability were also higher in BTC-28101.
- Table VI reports comparative Ig titers and concentration.
- Ig titers determined by titrating samples in a mouse Ig capture ELISA.
- Hybridoma cell line NP11 (anti-N-acetylprocainamide) was cultured in either BTC-28101 or DMEM. This cell line was slightly slower than the other cell lines to respond to BTC-28101 with enhanced levels of antibody production; variations for different cell lines are not surprising. It is significant that the BTC-28101 culture produced substantial levels of antibody when cultures in DMEM were no longer viable. The ability to keep cultures producing for longer periods of time is a significant advantage of BTC-28101. See Table VII.
- EXAMPLE 8 Spinner Flask Experiments with BTC 28101 Medium Anti-theophylline hybridoma cells were inoculated into 250 ml of Difco's preparation of BTC 28101 or DMEM at 2 x 10 5 cells/ml in 500 ml spinner flasks. Both media were supplemented with 10% FBS, 2% L-glutamine, and 1% pen-strep. Five ml samples were collected from each flask on the days indicated. Cell viability was determined each day samples were collected, and antibody concentrations were determined for all samples by radial immunodiffusion (RID) after all had been collected. Until that time, the samples (with cell material removed by centrifugation) were stored at -20°C. Antibody concentrations, as determined by RID, and cell viabilities are described in Table IX:
- the cell line utilized produced 1 mg/ml under conditions described. Specifically, the spinner flasks did not provide ideal culture conditions. Once the experiment was set up, the medium was never replaced or replenished. Consequently, metabolites and dead cells continued to accumulate.
- EXAMPLE 9 Anti-theophylline hybridoma cells were inoculated into 100 ml of Difco' s preparation of BTC 28101 or in- house medium (DMEM) at 2 x 10 5 cells/ml in 250 ml spinner flasks. All other parameters were as described in Example 8. Antibody concentrations, as determined by RID, and cell viabilities are described in Table X:
- Example 9 the culture volume in Example 9 was one- half that in Example 8. Consequently, nutrients may have depleted more quickly and metabolites or other materials accumulated in inhibitory concentrations more rapidly.
- Hybridoma 2HG11 has been adapted to serum-free conditions in the respective media. All media were supplemented with insulin, transferrin, ethanolamine and selenite. Cells were inoculated into 100 ml of BTC-28101 or control media at 2xl0 5 /ml in 250 ml shaker flasks.
- Medium BTC-28101 was further enhanced to formulate Medium-28102.
- Component (C) was prepared according to the composition in Table XI and milled to dry fine powder. The powder was sterilized by gamma-irradiation and added to 100 ml of BTC-28101, constituting the Medium BTC-
- Osmolarity of the medium was around 400 mOsm/Kg.
- Cystine is utilized in lieu of cysteine which is toxic to cells at high concentration.
- composition of medium BTC-28102 is: Glucose 10.269 g/1
- Inoculum cells were adapted to Medium BTC-28101 following the protocol stated in Example 2 and inoculated at 2xl0 5 /ml when starting the shaker batch, along with the control cells in 100 ml of DMEM/F12 medium. The effects on cell growth are shown in Fig. 4. Maximum concentration of Ig in the culture are summarized in Table XII.
- BTC-28103 was prepared as in BTC- 28101 but the buffer contents of HEPES and NaHCO were increased to 8330 mg/1 and 2650 mg/1, respectively. As a result, osmolarity of the medium was increased to 360 mOsm/Kg.
- CHO (Chinese Hamster Ovary) cells were adapted to grow in suspension and cultured in 100 ml of BTC-28103 and the control IMDM in shaker flasks, both supplied with 10% FBS, thymidine and hypoxanthine . Growth of the cultures was followed daily by hemocytometer counting and presented in Fig. 5.
- the media of the invention is useful to culture protein expressing cell lines in the various forms of available bioreactors.
- media of this invention may be used as the intracapillary medium in hollow fiber bioreactor culture of recombinant protein expressing CHO cells.
- Table XIII indicates the composition of the commercially available media RPMI , D/F and eRDF and of the 28101 (Example 1) and 28102 (Example 11) media of the invention. Table XIII
- a novel cell culture media which improves protein production by cells of all types including mammalian cells which express recombinant protein vectors has been disclosed.
- the invention will substantially enhance the cost effectiveness of cell culture procedures generally including the production of monoclonal antibodies.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP54212698A JP2002501374A (en) | 1997-04-07 | 1998-04-07 | Cell culture media for enhanced protein production |
CA 2286323 CA2286323C (en) | 1997-04-07 | 1998-04-07 | Cell culture media for enhanced protein production |
EP98915312A EP0973867A4 (en) | 1997-04-07 | 1998-04-07 | Cell culture media for enhanced protein production |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/833,500 | 1997-04-07 | ||
US08/833,500 US20020012991A1 (en) | 1997-04-07 | 1997-04-07 | Cell culture media for enhanced protein production |
Publications (1)
Publication Number | Publication Date |
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WO1998045411A1 true WO1998045411A1 (en) | 1998-10-15 |
Family
ID=25264584
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/US1998/006800 WO1998045411A1 (en) | 1997-04-07 | 1998-04-07 | Cell culture media for enhanced protein production |
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US (3) | US20020012991A1 (en) |
EP (1) | EP0973867A4 (en) |
JP (1) | JP2002501374A (en) |
CA (1) | CA2286323C (en) |
WO (1) | WO1998045411A1 (en) |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1549678A2 (en) * | 2002-09-30 | 2005-07-06 | Pfizer Products Inc. | Hybridomas producing high levels of human sequence antibody |
EP1551988A2 (en) * | 2002-07-19 | 2005-07-13 | Morphotek Inc. | Methods for generating enhanced antibody-producing cell lines with improved growth characteristics |
WO2006026445A1 (en) * | 2004-08-27 | 2006-03-09 | Wyeth Research Ireland Limited | Production of polypeptides |
US7300773B2 (en) | 2004-08-27 | 2007-11-27 | Wyeth Research Ireland Limited | Production of TNFR-Ig |
US7335491B2 (en) | 2004-08-27 | 2008-02-26 | Wyeth Research Ireland Limited | Production of anti-abeta |
US20140314779A1 (en) * | 2013-03-15 | 2014-10-23 | Genentech, Inc. | Cell culture compositions with antioxidants and methods for polypeptide production |
WO2016156476A1 (en) * | 2015-04-01 | 2016-10-06 | Boehringer Ingelheim International Gmbh | Cell culture medium |
EP2154244B1 (en) | 2007-04-26 | 2017-04-12 | Chugai Seiyaku Kabushiki Kaisha | Cell culture method using amino acid-enriched medium |
EP2563906B1 (en) | 2010-04-26 | 2017-11-08 | Novartis AG | Process for cultivation of cho cells |
US10927342B2 (en) | 2015-08-04 | 2021-02-23 | Regeneran Pharmaceuticals, Inc. | Taurine supplemented cell culture medium and methods of use |
US11292829B2 (en) | 2011-07-01 | 2022-04-05 | Amgen Inc. | Mammalian cell culture |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1482031B1 (en) * | 1996-08-30 | 2015-10-28 | Life Technologies Corporation | Serum-free mammalian cell culture medium, and uses thereof |
US20020012991A1 (en) * | 1997-04-07 | 2002-01-31 | Florence Chua Nee Ho Kit Fong | Cell culture media for enhanced protein production |
EP1707634A1 (en) * | 2005-03-29 | 2006-10-04 | Octapharma AG | Method for isolation of recombinantly produced proteins |
US20130281355A1 (en) | 2012-04-24 | 2013-10-24 | Genentech, Inc. | Cell culture compositions and methods for polypeptide production |
US10119117B2 (en) | 2016-01-28 | 2018-11-06 | Nanogen Pharmaceutical Biotechnology Co., Ltd | Universal, glycosylation enhancer, completely chemically defined medium formulation |
WO2018018613A1 (en) * | 2016-07-29 | 2018-02-01 | 广东东阳光药业有限公司 | Cell culture medium and culture method for increasing purity of antibody |
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-
1997
- 1997-04-07 US US08/833,500 patent/US20020012991A1/en not_active Abandoned
-
1998
- 1998-04-07 WO PCT/US1998/006800 patent/WO1998045411A1/en not_active Application Discontinuation
- 1998-04-07 CA CA 2286323 patent/CA2286323C/en not_active Expired - Lifetime
- 1998-04-07 EP EP98915312A patent/EP0973867A4/en not_active Withdrawn
- 1998-04-07 JP JP54212698A patent/JP2002501374A/en not_active Ceased
-
2002
- 2002-10-04 US US10/264,979 patent/US7601535B1/en not_active Expired - Fee Related
-
2009
- 2009-10-12 US US12/577,666 patent/US20100093039A1/en not_active Abandoned
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EP1551988A2 (en) * | 2002-07-19 | 2005-07-13 | Morphotek Inc. | Methods for generating enhanced antibody-producing cell lines with improved growth characteristics |
EP1551988A4 (en) * | 2002-07-19 | 2007-11-14 | Morphotek Inc | Methods for generating enhanced antibody-producing cell lines with improved growth characteristics |
EP1549678A4 (en) * | 2002-09-30 | 2006-01-18 | Pfizer Prod Inc | Hybridomas producing high levels of human sequence antibody |
EP1549678A2 (en) * | 2002-09-30 | 2005-07-06 | Pfizer Products Inc. | Hybridomas producing high levels of human sequence antibody |
WO2006026445A1 (en) * | 2004-08-27 | 2006-03-09 | Wyeth Research Ireland Limited | Production of polypeptides |
US7294484B2 (en) | 2004-08-27 | 2007-11-13 | Wyeth Research Ireland Limited | Production of polypeptides |
US7300773B2 (en) | 2004-08-27 | 2007-11-27 | Wyeth Research Ireland Limited | Production of TNFR-Ig |
US7335491B2 (en) | 2004-08-27 | 2008-02-26 | Wyeth Research Ireland Limited | Production of anti-abeta |
EP2357250A3 (en) * | 2004-08-27 | 2014-07-02 | Pfizer Ireland Pharmaceuticals | Production of polypeptides |
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WO2016156476A1 (en) * | 2015-04-01 | 2016-10-06 | Boehringer Ingelheim International Gmbh | Cell culture medium |
US11312936B2 (en) | 2015-08-04 | 2022-04-26 | Regeneron Pharmaceuticals, Inc. | Taurine supplemented cell culture medium and methods of use |
US10927342B2 (en) | 2015-08-04 | 2021-02-23 | Regeneran Pharmaceuticals, Inc. | Taurine supplemented cell culture medium and methods of use |
Also Published As
Publication number | Publication date |
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EP0973867A1 (en) | 2000-01-26 |
CA2286323A1 (en) | 1998-10-15 |
EP0973867A4 (en) | 2002-12-04 |
US20020012991A1 (en) | 2002-01-31 |
CA2286323C (en) | 2010-06-15 |
US7601535B1 (en) | 2009-10-13 |
JP2002501374A (en) | 2002-01-15 |
US20100093039A1 (en) | 2010-04-15 |
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